Isoxazolo(5,4-b)pwridines,5,6 - polymethyleneisoxazolo(5,4 - b)pyridines and processes therefor



United States Patent O US. Cl. 260-288 6 Claims ABSTRACT OF THE DISCLOSURE This invention relates to isoxazoles and to processes for their preparation. It is more particularly directed to isoxazolo[5, 4-b]pyridines represented by the formula wherein R is selected from the group consisting of loweralkyl, phenyl, lower-alkylphenyl, lower-alkoxyphenyl, and halophenyl, R has the same meaning as R and in addition hydrogen; and 5,6-polymethyleneisoxazolo[5,4-b1pyridines of the formula f 5//4\ CH3 on n 2) 7 12N N o (la) wherein R" is selected from the group consisting of phenyl, lower-alkylphenyl, lower-alkoxyphenyl and halophenyl, n is an integer of from 3 to 6, inclusive; also the acid addition salts of the compounds embraced by the above Formulae I, Ia. The compounds of Fomula I are useful as anti-fungals while those of Formula Ia are useful as anti-inflammatories.

As use in this specification, the term lower-alkyl means alkyl of from 1 to 4 carbon atoms, inclusive, e.g., methyl, ethyl, propyl, butyl, and isomeric forms thereof; the term halophenyl means halogen-substituted phenyl wherein the halogen is selected from chlorine, bromine, iodine, and fluorine; the term lower-alkoxyphenyl means phenyl substituted with one or more alkoxys of from 1 to 4 carbon atoms, inclusive, e.g., methoxyphenyl, trimethoxyphenyl, ethoxyphenyl, propoxyphenyl, butoxyphenyl, dibutoxyphenyl, and isomeric forms thereof; the term lower-alkylpheny means phenyl substituted with one or more alkyls of from 1 to 4 carbon atoms, inclusive, e.g., toyl, xylyl, trimethylphenyl, ethylpheny, butylphenyl, and isomeric forms thereof.

'ice

The novel isoXazolo[5,4-b]pyridines of Formulae I and Ia exist either in the nonprotonated (free base) form or in the protonated (acid addition salt) form depending on the pH of the environment. They form stable protonates, i.e., acid addition salts, on neutralization with suitable acids, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, acetic, benzoic, salicylic, glycolic, succinic, nicotinic, tartaric, maleic, malic, pamoic, methanesulfonic, cyclohexanesulfamic, picric, and lactic acids, and the like. These acid addition salts are useful for upgrading the free bases. The free bases are useful as acid acceptors in neutralizing undesirable acidity or in absorbing an acid as it is formed in a chemical reaction, for example, a dehydrohalogenation reaction in which hydrogen and chlorine, bromine, or iodine are removed from vicinal carbon atoms.

The novel Formula I and Formula Ia compounds form salts with fluosilicie acid which are useful as mothproofing agents according to US. Pat. 1,915,334 and 2,075,359. They also form salts with thiocyanic acid which condense with formaldehyde to form resinous materials useful as pickling inhibitors according to US. Pat. 2,425,320 and 2,606,155. They also form salts with trichloroacetic acid which are useful as herbicides, for example, against Johnson grass, yellow foxtail, green foxtail, Bermuda grass, and quackgrass.

The novel isoxazolo[5,4-b]pyridines of Formula I are prepared by treating the known compound 5-amino-3- methylisoxazole of the Formula FTC/H3 H N 5 2N with a corresponding diketone of the formula i n RC-GHCR (III) wherein R and R have the same meaning as above, in the presence of an acid catalyst.

5-arnino-3-methylisoazole (II) is known in the art; it can be prepared by reacting S-iminobutyronitrile with hydroxylamine; also by the procedure described in Ann. 624, 22 (1959).

The diketones of Formula III are well known in the art and a wide variety of them have been prepared by known methods, e.g., in accordance with Organic Syntheses 20, 32 (1940) and volume VIII, page 133 of Organic Reactions, John Wiley and Sons, Inc., New York, 1954. Among the known diketones that can be employed in the novel process are 1,3-diphenyl-1,3-propanedione; 1,3-di(p-tolyl)-1,3-propanedione; 1,3-di(m-chlorophenyl) 1,3 propanedione; 1,3-di(p-chlorophenyl)-l,3- propanedione; 1,3 di(p-methoxyphenyl) 1,3-propanedione; l,3-di(p-bromophenyl)-l,3-propanedione; 2,4-pentanedione; 3-methyl-2,4-pentanedione; 3-ethyl-2,4-pentanedione; 3-buty1-2,4-pentanedione; 3-phenyl-2,4-pentanedione; 3-isopropyl-2,4-pentanedione; 3-isobultyl-2,4-pentanedione, and the like. Representative starting materials of The novel 5,6-polymethyleneisoxazolo[5,4-b]pyridines Formula III and publications describing their preparation of Formula la are prepared by treatmg -am1no-3-methylare set forth in the table that follows. isoxazole (II) with a corresponding Z-benzoylcycloalkanone of the formula 5 i? ll I uo11 on" Starting material (111) lubhentlon K (Cllm 3 111eth)"l-2,4-pentancdione J. Amcjr. Chem. Soc., 77, 1754 1055. 3 1thyl-ZA-perflancdione J. Soc. Cl1o111.l11(l.,44, 462T (1925); Whelcln R n h the snne meaning [5 Above 1] named 3-etl1ylaeetylacetone. I the presence of an and catalyst. figaf gmmifm The 2-benzoylcycloalkanones of Formula Illa wherein 10110. L R is benzoyl or substituted benzoyl, many of which are 3-150110 )yl-Z'l-pentancdimm J. Amer. Chem. Soc. 72, 36 10 l 1 (1950); named isopropylacetyb known, can be prepa1ed 1n accoldance w1th the methods acetone (IX). descnbed 1n Ann. 650, 133-156 (1961); J. Amer. Chem. 3-is0butyl-lA-pentanedione J.(1.5151(1)1)er. Chem. 800., 72, 3635 82, 2389 2393 (1960); J. g Chenl 28 379 383 1,3di(p-tolyl)-1,3-propa11edione Part of Example 2 01' US. (1963). Among the known Z-lJCIlZOYlCYClOZllkfll'lOIlCS that Patent3203,594. 1,3-di(m-ehlorophenyl)-1,3- Cl1e1n.l3c1 .,86,12(l3 (1052). be employed m the novel process are 2 (p methyl propanedionc (r v Q benzoyl)cyclopentanone, Z-(p-methoxybenzoyl)cyclopengggfigggg 607 L63 tanone, 2-(p-iodobenzoyl)cyclopentanone, Z-benzoyleyclo- 1, -d (pp l- A1111-,G18,110(1058). hexanone, 2-(m-chlorobenzoyl)cyclohexanone, 2-(p-fluopropanedione 1,3-(1i(p-methoxyphenyl)-1,3- Cl1em.Ber.,84,G07 1951). robenloyncyclohexanonei 2 (P methoxybenzoyhcyclo 3 pi'opanedono J A C1 8 66 1200 hexanone, 2-benzoylcycloheptanone, Z-benzoylcyclooctan- ,5-1e )tane ione mer. 10. 0c., s 4G n0{mnedi0n0 Ark, Kemp 3 365 (1951, one, and the l1ke. Representatwe starting matenals of 2.6-di11mthyl-3Mwptime Arknh 6 1 0845 9, Formula Illa and publ1cat1ons descnbmg the1r preparar" """undocamdwne 3 5 0 non are set forth in the table that follows. 2,S-dimethylAfi-nonancdione Org. Syntheses, 28, 44 (1948); J. Amer. Chem. Soc, 72, 1352 (1950); flamed dllsovalcl'yl Starting material (Illa) Publication methane 111 both. y p J- Amer- Chem- S09, 1 901 (1951)- 2-be zoylcyclooetanone J, Org, Chem 24,583 (1955)),

10119 2- wth 11121120 1 c 'clooctanone. J. O1".Cl11n., ..l,83 111'!) 4-methyl-3,5 heptanedione .J. Org. 0110111., 23, 879 (15158). (l L y L y) I i gt i 2-ethyl-1,3-diphenyl-1,3-propanelun rlger. Chem. Soc, 73, 5660 ocumonm J" 2-11enzoylcyeloheptanonc J.Org.Cl1en1. 21, 583 (1959). l i 'p p J- Amcn (3116- 9-; 271 0531 (1955) 2-hcnzoylcycloliexan0 1e J',A1ner Cl1o1n.Soe., 78, 6066 (1956),

(collllmund e\\\)i J 011$ 2-(p-methylbenzoyl)cyelo- J.Amer.Cl1e1n.Soe.,82,2380 (1960). 0110111., 4, 93 (1939), named hexfluone Pheny]dlhenzoylnletllanci J- 2 (p-propyll1enz0yl)cyclo- J.Amer.Cl1em.Soc., G7 284 (1945);

Chem- 020 (1915), hexanone named 2-butyrylcyclohexanm1e.

na e d be m. nhenylnwthmw 2-(111 etl1oxybenzoyDcyelo- I.An1er.Chen1Soc., 78. 6066 (1956) 1,3-d1(p-lluorophenyl)-1,3 propa11e- A1111., 018, 110 (1908). hexanoue discloses corresponding (110,119 p-methoxy isomer (named 2- 1,13-d1-(p-1odophenyl)-l,3-pr0pane- 111111., 618, 110 (1958). anisoyleyclolwxanone).

. 2( chlorobenz0yl)eyclohexauone J.Amer.Chem.Soc. 82, 238!) (1960). 1r3'dlmv4dllnoumxyphcnynlla Chem 3 T' on; Q-(S-bromobenzoyl)eyelohcxanone J.Amer.Chem.Soc.: 82, 238! (1960) propancdmne Chen1.,24, 1b, 1581 (lJoJ). 40 discloses corresponding 048mm 2-benz0yleyclopentanone J.Ame1'.Chem.Soe., 78, 6066 (11156).

2-(p etl1ylbcnzoyDcyeIo- Chem.Ber., 93, 901! (1061)); named pentanone 2-propionyleyelopentanone.

2-(m-methoxy)cyelopentanone J.Amer.Chnm.Soe., 78, 6066 (1951i) discloses corresponding pison1er Stntable ac1d catalysts 1nclude, for example, concen- (named Q-anisoylcyelotrated sulfuric acid, phosphorus pentoxide, phosphorus pcnmmmh pentachloride, polyphosphoric acid and the like, the lattermost being preferred. Suitable acid catalysts include those employed in the In carrying out the reaction between y preparation of the compounds of Formula I, recited above. isoxazole (II) and the diketone of Formula III, the two The method of preparing the 5,6-polymethylene isoxreactants are mixed with the acid catalyst and the mixazolo[5,4-b]pyridines of Formula la and their acid additure heated, e.g., between about 50 C. to about 175 0, tion salts, namely, by treating 5-amino-3-methylisoxazole preferably between about 100 C. to about 140 C. Inert (II) with a corresponding 2-benzoylcycloalkanone (Illa) solvents are not necessary but can be employed, if desired. in the presence of an acid catalyst, employs the same pro- The molecular ratio of the compounds of Formula II cedures under the same conditions as in the synthesis of and Formula III can be varied, equimolar ratios of about the compounds of Formula I described above; the only 1:1 having been found satisfactory. The time required difference is that 2-benzoylcycloalkanones (Illa) are used for the completion of the reaction depends upon such instead of the diketones of Formula Ill. factors as the reaction temperature, the particular react- The novel compounds of Formulae l and la, in their ants employed, the relative amounts of reactants, thorfree base form and in the form of their acid addition oughness of mixing, and the like. Therefore, it will be salts with pharmacologically acceptable acids, for exunderstood that the optimum reaction time will vary ample, hydrochloric, hydrobromic, sulfuric, phosphoric,

for each set of reaction conditions. Ordinarily, reaction nitric, acetic, benzoic, salicylic, glycolic, succinic, nicotimes ranging from about 10 minutes to about 1 hour tinic, tartaric, maleic, malic, lactic, methanesulfonic, and are suitable. After completion of the reaction, the reaccyclohexanesulfamic acids, and the like, exhibit biological tion mixture is diluted with water and neutralized with a activity. The compounds of Formula I possess anti-fungal base (e.g., ammonium hydroxide) and the thus-produced properties. lllustratively, they inhibit the growth of the isoxazolo[5,4-b]pyridine of Formula I isolated from the pathogen Trichoplzyton rubmm and can be used in the reaction mixture in its free base form, using conventreatment of infections due to this microorganism in mamtional procedures such as filtration, solvent evaporation, mals and animals, e.g., cats and dogs. These compounds solvent extraction, chromatography or crystallization, or are also eficctive herbicides and can be used in the cona combination of these methods. Each of the free bases so trol of crabgrass, quackgrass, bindweed, pigwced and obtained can be purified, e.g., by recrystallization from a lambquarters. The compounds of Formula Ia possess antisuitable solvent or pair of solvents. The free base can be inflammatory activity; they can be used in the treatment of converted to any desired acid addition salt by neturalizainflammatory conditions of the skin, eyes and respiratory tion with an acid, e.g., any of those given above. tract of mammals and animals, e.g., mice, rats and birds.

The following examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.

EXAMPLE 1 3,4,6-trimethylisoxazolo[5,4-b1pyridine (I) A mixture of 98 g. (1 mole) of -amino-3-rnethylisoxazole (II) and 110 ml. (1.07 moles) of acetylacetone (alternatively named 2,4-pentanedione) in about 150 ml. of polyphosphoric acid was warmed to 30 C. and then cooled rapidly in an ice bath. The temperature of the reaction mixture rose rapidly to 140 C. despite the external cooling. It was stirred at this temperature for about 15 minutes and then cooled to room temperature. Then, with cooling, 500 ml. of water and concentrated ammonium hydroxide was added until the solution was at pH 8. The mixture was cooled to 5 C. and filtered. The solid was recrystallized from 800 ml. of a mixture of equal parts of isopropanol and water to give 105 g. (65% yield) to 3,4,6-trimethylisoxazolo[5,4-b1pyridine (I), melting at 92 to 93 C.

Analysis.-Calcd. for C H N O (percent): C, 66.22; H, 6.22; N, 17.27. Found (percent): C, 66.62; H, 6.26; N, 17.26.

Infrared and nuclear magnetic resonance (NMR) spectra support the structure of the thus-produced compound.

The addition of a diethyl ether solution of hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, benzoic acid, salicyclio acid, citric acid, succinic acid, malic acid, cyclohexanesulfamic acid, thiocyanic acid or trichloroacetic acid, etc. to an ethanol solution of 3,4, 6-trirnethylisoxazolo[5,4-b]pyridine, followed by addition of about 4 volumes of diethyl ether, gives the corresponding acid addition salt.

EXAMPLE 2 3,4,6 -trimethyl-S-phenylisoxazolo[5,4-b1pyridine (H) A mixture of 9.8 g. (0.1 mole) of 5-amino-3-methylisoxazole (II) and 20 g. (0.11 mole) of 3-phenyl-2,4- pentanedione in about 25 ml. of polyphosphoric acid was warmed slowly to about 100 C. at which point it rose rapidly to about 155 C. The reaction mixture was heated at 140 to 160 C. for a half hour, then cooled. Then 200 ml. of water and concentrated ammonium hydroxide were added until the reaction mixture was neutral. The brown solid was separated by filtration. This material was recrystallized twice from ethanol with decolorizing charcoal treatment to give 12.5 g. (53% yield) of 3,4,6- trimethyl-S-phenylisoxazolo [5,4-b] pyridine (I), melting at 208.5 to 210 C.

Analysis.-Calcd. for C H N O (percent): C, 75.60; H, 5.92; N, ll.7 6. Found (percent): C, 75.76; H, 5.93; N, 11.84.

Infrared and NMR spectra support the structure.

The addition of a diethyl ether solution of hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, 'benZOic acid, salicylic acid, citric acid, succinic acid, malic acid, cyclohexanesulfamic acid, thiocyanic acid or trichloroacetic acid, etc. to an ethanol solution of 3,4,6-trimethyl 5-phenylisoxazolo[5,4-b] pyridine, followed by addition of about 4 volumes of diethyl ether, gives the correspounding acid addition salt.

"EXAMPLE 3 3-methyl-4,6-diphenylisoxazolo [5,4-b] pyridine (I) A mixture of 9.8 g. (0.1 mole) of 5-amino-3-methylisoxazole (II) and 22.5 g. (0.1 mole) of 1,3-diphenyl 1,3-propanedione in about 25 ml. of polyphosphoric acid was heated slowly to 140 C. The temperature then rose rapidly to 160 C. The reaction mixture was kept at this temperature for 20 minutes, cooled and a large volume of water added. Then concentrated ammonium hydroxide was added until the reaction mixture was neutral. The solid was filtered and discarded. The filtrate was extracted with ether. The ether layer was dried and concentrate dunder vacuum. The residue was recrystallized from 250 ml. of isopropanol to give 2.7 g. (10% yield) of 3- methyl-4,6-diphenylisoxazolo[5,4-b]pyridine (I), melting at 157 to 158.5 C.

Analysis.Calcd. for C H N O (percent): C, 79.70; H, 4.93; N, 9.78. Found (percent): C, 79.59; H, 4.72; N, 9.83.

Infrared and NMR spectra support the structure.

Following procedures similar to those of Examples 1, 2 and 3 and the general methods for preparing the compounds of Formula I described above, but employing the following diketones; 3-methyl-2,4-pentanedione, 3-ethyl-2,4-pentanedione, 3-butyl-2,4-pentanedione, 3-isopropyl-2,4-pentanedione, 3-isobutyl-2,4-pentanedione, 1,3-di(p-tolyl)-1,3-propanedione, 1,3-di(m-chloropheny1)-1,3-propanedione, 1,3-di(p-chloropenyl) -1,3-propanedione, 1,3-di(p-bromophenyl)-1,3-propanedione,

, l,3-di(p-methoxyphenyl)-1,3-propanedione,

3,5 -heptanedione,

4,6-nonanedione,

2,6 -dimethyl-3 ,5 -heptanedione,

5 ,7-undecanedione,

2, 8-dimethyl-4,6-nonanedione,

2,2,6 ,6-tetramethyl-3 ,5 -heptanedione, 4-methyl-3 ,5 -heptanedione, 5-ethyl-4, 6-nonanedione,

2-ethyl-1,3 -diphenyl-1,3-propanedione,

1,2, 3-triphenyl-1, 3 -propanedione,

1,3 -diphenyl-2-(p-to1yl)-1, 3-p rop anedione, 1,3-di(p-fluorophenyl)-1,3-propanedione, 1,3-di(p-iodophenyl) -1,3-propanedione, 1,3-dimesityl-1,3-propanedione,

1,3 -di (2,4-dimethoxyphenyl) -1,3-propanedione, and 1,3-di(2,4,6-trichlorophenyl) -1,3-propanedione,

yield, respectively,

3 ,4,5,6-tetramethylisoxazolo [5 ,4-b pyridine,

3 ,4,6-trin1ethyl-5 -ethylisoxazolo [5 ,4-b] pyridine,

3 ,4,6-trimethyl-S-butylisoxazolo [5 ,4-b 1 pyridine,

3,4,6-trimethyl-5-isopropylisoxazolo [5,4-b] pyridine,

3 ,4,6-trimethyl-5-isobutylisoxazolo [5 ,4-b] pyridine,

3-methyl-4,6-di (p-tolyl) isoxazolo [5,4-b pyridine,

3-methyl-4,6-di (m-chlorophenyl) isoxazolo [5 ,4-b] pyridine,

3 -methyl-4,6-di(pchlorophenyl) is oxazolo [5,4-b] pyridine,

3 -rnethyl-4,6-di (p'bromophenyl) isoxazolo 5,4-b]

pyridine, I

3-methyl-4,=6-di (p-methoxyphenyl) isoxazolo 5,4-b]

pyridine,

3-methyl'4,6-diethylisoxazolo [5 ,4-b] pyridine,

3-methyl-4,6-dipropylisoxazolo [5 ,4-b] pyridine,

3 -methyl-4,6-diisopropylisoxazolo [5 ,4-b] pyridine,

3-methyl-4,'6-dibutylisoxazolo [5 ,4-b] pyridine,

3 -methyl-4, 6-diisob utylisoxazolo [5 ,4-b pyridine,

3 -methyl-4,6-di-t-butylisoxazolo [5 ,4-b pyridine,

3 ,5 -dimethyl-4, 6-diethylisoxazolo [5 ,4-b] pyridine,

3-methyl-4,6-dipropyl-5 -ethylis oxazolo [5 ,4-b pyridine,

3 -methyl-4, 6-diphenyl-5 -ethylisoxazolo [5,4-b] pyridine,

3 -methyl-4,5 6-triphenylisoxazolo [5 ,4-b pyridine,

3 -methyl-4, 6-diphenyl-5 p-tolyl) is oxazolo [5 ,4-b]

pyridine,

3 -methyl-4,'6-di (p-fluorophenyl) isoxazolo [5 ,4-b]

pyridine,

3 -methyl-4, 6-di (p-io dophenyl) isoxazolo [5,4-b pyridine,

3-methyl-4,6-dimesitylisoxazolo [5,4-b pyridine,

3 -methyl-4,6-di 2,4-dimethoxyphenyl) isoxazolo [5 ,4-b]

pyridine, and

3-methyl-4,6-di(2,4,6-trichlorophenyl) isoxazolo [5,4-b]

pyridine.

The addition of a diethyl ether solution of hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, benzoic acid, salicylic acid, citric acid, succinic acid, malic acid, cyclohcxanesulfamic acid, thiocyanic acid or trichloroacetic acid, etc. to an ethanol solution of an isoxazol[5,4-b]pyridine set forth in the preceding paragraph, followed by addition of about 4 volumes of diethyl ether, gives its corresponding acid addition salt.

EXAMPLE 4 4- (p-methoxyphenyl -3-methyl-5,6-tetramethyleneisoxazolo[5,4-b] pyridine (In) A mixture of 9.8 g. (0.1 mole) of -amino-3-methylisoxazolo (II) and 23.2 g. (0.1 mole) of 2-(p-methoxybenzoyl)cyclohexanone in about 25 ml. of polyphosphoric acid was heated to about 70 C., at which point the temperature started to rise rapidly. The reaction mixture was cooled, again heated to about 120 C. when the temperature again rose rapidly. The reaction mixture was cooled, then heated to 130 to 150 C. for half an hour, again cooled and 250 ml. of water and concentrated ammonium hydroxide added until it was slightly alkaline. The reaction mixture had 1 l. of water added to it and then was extracted 3 times with chloroform. The organic layer was dried and concentrated to dryness. The residue was recrystallized three times from isopropanol (decolorizing charcoal treatment) to give 6.5 g. (22% yield) of white 4-(p-methoxyphenyl)-3-methyl 5,6 tetramethyleneisoxazolo[5,4-b]pyridine (Ia) melting at 160.5 to 162.5 C.

AnaIysis.-Calcd. for C H N O (percent): C, 73.45; H, 6.16; N, 9.52. Found (percent): C, 73.44; H, 6.49; N, 9.39.

Infrared and NMR spectra support the structure.

Following the procedures similar to that of Example 4 and the general methods for preparing the compounds of Formula Ia described above, but employing the following Z-benzoylcycloalkanones:

Z-benzoylcyclooctanone,

2- (p-ethylbenzoyl cyclooctanone,

2- (m-isopropylbenzoyl cyclooctanone, 2- (o-butylbenzoyl cyclooctanone,

2- p-ethxybenzoyl cyclooctanone,

2- m-isobutoxyb enzoyl cyclooctanone, 2-(o-fiuorobenzoyl cyclooctanone,

2- (m-iodobenzoyl cyclooctanone, Z-benzoylcycloheptanone,

2- o-methylbenzoyl cycloheptanone, 2- (m-propylbenzoyl cycloheptanone, 2- p-isobutylbenzoyl cycloheptanone, 2- p-methoxybenzoyl cycloheptanone, 2- (o-butyoxybenzoyl cycloheptanone, 2- (m-chlorobenzoyl cycloheptanone, 2- p-bromob enzoyl cycloheptanone, 2-benzoy1cyclohexanone,

2- (p-methylbenzoyl cyclohexanone,

2- m-propylbenzoyl cyclohexanone, 2- p-isobutylbenzoyl cyclohexanone, 2- (m-ethoxybenzoyl cyclohexanone, 2- (p-propoxybenzoyl cyclohexanone, 2- (p-chlorobenzoyl cyclohexanone,

2- (m-bromobenzoyl) cyclohex anone, 2-benzoylcyclopentanone, Z-(p-ethylbenzoyl)cyclopentanone,

2-(1n-isopropylbenzoyl cyclopentanone,

2- o-butylbenzoyl cyclopentanone,

2- (m-methoxybenzoyl cyclopentanone, 2-( p-isobutoxybenzoyl)cyclopentanone, 2- (o-chlorobenzoyl cyclopentanone, and 2-(p-iodobenzoyl cyclopentanone,

yields, respectively,

4-phenyl-3-methyl-5,6-hexamethyleneisoxazolo[5,4-b]

pyridine,

4- (p-ethylphenyl -3-methyl-5,6-hexamethyleneisoxazolo- [5,4-b]pyridine,

4-( m-isopropylphenyl -3-methyl-5,6-hexamethyleneisoxazolo- [5,4-b] pyridine,

4-(o-butylphenyl)-3-methy1-5,6-hexamethyleneisoxazolo- [5,4-b] pyridine,

4-(p-ethoxyphenyl)-3-methyl-5,6-hexamethyleneisoxa zolo-[5,4-b]pyridine,

4-(1n-isobutyoxyphenyl) -3-methyl-5,6-hexarnethyleneisoxazolo-[5,4-b] pyridine,

4-(o-fluorophenyl)-3-methyl-5,6-hexamethyleneisoxazolo- [5,4-b]pyridine,

4-(1n-iodophenyl)-3-methyl-5,6-hexamethylencisoxazolo- [5,4-b] pyridine,

4-phenyl-3-methyl-5,6-pentamethyleneisoxazolo[5,4-b]

pyridine,

4- (o-tolyl) -3-methyl-5,6-pentamethyleneisoxazolo[5,4-

bJpyridine,

4-(m-propylphenyl)-3-methyl-5,6-pentamethyleneisoxazolo[5,4-b]pyridine,

4-(p-isobutylphenyl)-3-methyl-S,6-pentamethyleneisoxazolo [5,4-b] pyridine,

4-(p-methoxyphcnyl)-3-methyl-5,6-pentamethyleneisoxazolo [5,4-b] pyridine,

4-(o-butoxyphenyl )-3-methyl-5,6-pentamethyleneisoxazolo [5,4-b] pyridine,

4-( m-chlorophenyl)-3-methyl-5,6-pentamethyleneisoxazolo[5,4-b] pyridine,

4- p-bromophen yl -3 -methyl-5 ,G-pentamethyleneisoxazolo [5,4-b] pyridine,

4-phenyl-3 -methyl-5 ,6-tetramethyleneisoxazolo [5 ,4-b]

pyridine,

4-(p-tolyl)-3-methyl-5,6-tetramethyleneisoxazolo[5,4-b]

pyridine,

4-(m-propylphenyl)-3-methyl-5,6-tetramethyleneisoxazolo 5,4-b pyridine,

4-(p-isobutylphenyl) -3-methyl-5,6-tetramethyleneisoxazolo [5,4-b] pyridine,

4-(m-ethoxyphenyl)-3-methyl-5,G-tetramethyleneisoxazolo [5,4-b]pyridine,

4- p-propoxyphenyl -3-n1ethyl-5 ,G-tetramethyleneisox azolo [5,4-b pyridine,

4-(p-chlorophenyl)-3-methyl-5,6-tetramethylenei soxazolo [5 ,4-b pyridine,

4-(m-bromophenyl)-3-methyl-5,6-tetramethyleneisoxazolo [5,4-b]pyridine,

4-phenyl-3methyl-5,6-trimethyleneisoxazolo [5,4-b]

pyridine,

4- (p-ethylphenyl)-3-methyl-5,6-trimethyleneisoxazolo- [5,4-b]pyridine,

4-(m-isopropylphenyl)-3-methyl-5,6-trimethyleneisoxaZolo[5,4-b] pyridine,

4- (o-butylphenyl)-3-methyl-5,6-trimethyleneisoXaZolo[5,4-b]pyridine,

4-(m-methoxyphenyl)-3-methyl-5,6-trimethyleneisoxazolo[5,4-b]pyridine,

4-(p-isobutoxyphenyl)-3-methyl-5,6-trimethyleneisoxazolo [5,4-b1pyridine,

4-(o-chlorophenyl -3-methyl-5,6-trimethyleneisoxazolo[5,4-b]pyridine, and

4-(p-iodophenyl)-3-methyl-5,6-trimethyleneisoxazolo[5,4-b]pyridine,

The addition of a diethyl ether solution of hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid. acetic acid, benzoic acid, salicylic acid, citric acid, succinic acid, malic acid, cyclohexanesulfamic acid, thiocyanic acid or trichloroacetic acid, etc. to an ethanol solution of a 5,6-polymethyleneisoxazolo[5,4-b]pyridine set forth in the preceding paragraph, followed by addition of about 4 volumes of diethyl ether, gives its corresponding acid addition salt.

wherein R is selected from the group consisting of loweralkyl, phenyl, lower-alkylphenyl, loWer-alkoxyphenyl and halophenyl, wherein the lower-alkyl moiety of R is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl and secondary butyl, R has the same meaning as R and in addition hydrogen, and (2) an acid addition salt theerof.

2. A compound of claim 1 wherein R is methyl and R is hydrogen, namely, 3,4,6-trimethylisoxazolo[5,4-b] pyridine.

3. A compound of claim 1 wherein R is methyl and R is phenyl, namely, 3,4,6-trimethyl-S-phenylisoxazolo [5,4-b1pyridine.

4. A compound of claim 1 wherein R is phenyl and R is hydrogen, namely, 3-methyl-4,fi-diphenylisoxazolo [5,4-b1pyridine.

5. A compound selected from the group consisting of (1) a compound of the formula wherein R" is selected from the group consisting of phenyl, lower-alkylphenyl, lower-alkoxyphenyl and halophenyl, wherein the lower-alkyl moiety of R is selected from the group consisting of methyl, ethyl, propyl, isopropyl, isopropyl, butyl, isobutyl and secondary butyl, n is an integer of from 3 to 6, inclusive, and (2) an acid addition salt thereof.

6. A compound of claim 5 wherein R is p-methoxyphenyl and n is 4, namely, 4-(p-methoxyphenyl)-3- methyl-5,6-tetramethyleneisoxazolo [SA-b] pyridine.

References Cited UNITED STATES PATENTS 3,005,824 10/1961 Domagr 260-288 3,336,306 8/1967 Sulkowski 260288 X 3,381,016 4/1968 Markillie 260296 DONALD G. DAUS, Primary Examiner US. Cl. X.-R. 

